We have shown that the relative susceptibility of inbred mouse strains to DMH induced colonic tumors can be predicted by the indigenous proliferative characteristics of colonic epithelial cells of each strain. This proposal seeks to test the correlation between tumor incidence and cell proliferation using genetic and biochemical approaches. Firstly, matings of SWR (DMH-sensitive) and DBA (DMH-resistant) inbred strain will allow their F1, F2, and reciprocal backcrosses to be challenged with DMH for assessment of both tumor incidence and proliferative character. This should reveal if both properties are genetically linked as well as which type of proliferative character is domonant, i.e. a wide proliferative compartment (PC) and elevated labeling index (L.I.) or a narrow PC and low L.I.. Secondly, the contribution of metabolism to the carcinogenic response will be assessed in similar crosses using a) MAM, a metabolic of DMH and a direct acting carcinogen and b) MNU, a colon carcinogen not apparently dependent in metabolisms for activation. The proposal, therefore, investigates in depth a possible mechanism for the variable susceptibility of inbred mouse strains to DMH-induced tumorigenesis and seeks to explore the role of cell proliferation as a determinant in colonic tumorigenesis.
